Despite the ubiquity and importance of amide bonds, there are surprisingly few mechanistically distinct approaches to their preparation. For intermolecular couplings, amides are almost uniformly synthesized by the addition of an amine to an activated carboxylate. [1] This paradigm, which employs carboxylic acids and amines as starting materials, enables the widely employed methods of solid phase peptide synthesis and constitutes the basis for peptide assembly in biological systems. The notoriously poor functional group tolerance and chemoselectivity issues of condensation approaches have encouraged novel solutions to direct amidations with unprotected fragments under aqueous conditions. In this regard, the recent identification of the native peptide ligation reaction, which allows the chemoselective union of an N-terminal cysteine or related derivative and C-terminal thioesters, [2, 3] has dramatically impacted the synthetic accessibility of modified proteins and other complex amide based-structures. While important and widely used, this thioester ligation process is inherently constrained to substrates containing a free N-terminal sulfhydryl and more general alternatives are in great demand. [4,5]
An ideal peptide ligation would provide amide bonds by the direct coupling of unprotected precursors containing familiar but orthogonally reactive functional groups under aqueous conditions and without reagents, catalysts, or by-products. We now document this goal by the direct coupling of α-ketoacids and amine derivatives to afford native peptide bonds under mild, reagent-free conditions, producing only carbon dioxide and water or alcohol as by-products.